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18-MC Acts in the Medial Habenula and Interpeduncular Nucleus to Attenuate Dopamine Sensitization to

Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, is a potential treatment for drug addiction. 18-MC has been shown to decrease self-administration of drugs (e.g., morphine, methamphetamine, nicotine) and attenuate opioid withdrawal in rats. In previous studies, systemic pretreatment with 18-MC abolished the sensitized increase in accumbens dopamine levels induced by chronic morphine administration. In vitro studies have shown that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors, and alpha3beta4 antagonism is believed to be the primary mechanism responsible for 18-MC's effects on drug self-administration and possibly on morphine-induced changes in mesolimbic dopamine. While there are very low densities of alpha3beta4 nicotinic receptors in the mesolimbic pathway, these receptors are prominently localized in the medial habenula (MHb) and in the interpeduncular nucleus (IPN). These nuclei and the habenulo-interpeduncular pathway connecting them are believed to function as part of an alternate reward pathway modulating the dopaminergic mesolimbic pathway known to be involved in drug addiction. In the present study, to determine if 18-MC acts in the MHb or in the IPN, the effects of local infusion of 18-MC into these brain areas were assessed on mesolimbic dopamine responses to acute and repeated morphine treatment. Administration of 18-MC (10 mug) into either the IPN or MHb blocked the sensitized dopamine response to repeated morphine in the nucleus accumbens; 18-MC had no effect on the dopamine response to acute morphine. The results suggest that 18-MC acts in the habenulo-interpeduncular pathway to modulate the effects of repeated morphine in the dopaminergic mesolimbic system.